Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. One of our major focusses has been to understand whether LRRK2 mutations work by gain or loss of function. We have published recently that introducing a human mutation, G2019S, into the mouse genome causes activation of kinase activity and that this can be blocked pharmacologically using LRRK2 kinase inhibitors, which are now in phase I clinical trials for human PD. In parallel, we found many loss of function mutations in human PD cases but these were at a similar frequency in controls without PD. Putting these observations together, we propose that mutations in LRRK2 are likely to act in a dominant gain of function manner, supporting the idea that kinase inhibition will be clinically useful. We have also started to look at expression and activity of LRRK2 in non-neuronal cells, specifically microglia in the brain. We find that LRRK2 deficiency modestly but significantly reduces neuroinflammatory reactions of these cells. We therefore infer that LRRK2 inhibition will be helpful in mitigating microglial activation and we are currently trying to assess this hypothesis in vivo.